tbuckley/cabot-search huggingface dataset:
High-Intensity Interval Training vs Moderate-Intensity Continuous Training for Women Undergoing Cardiovascular Rehabilitation
Authors: Tasuku Terada, Sol Vidal-Almela, Jennifer L. Reed
Journal: JAMA Cardiology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
Abstract 1781: Up284, a novel inhibitor to treat quadruple negative breast cancer
Authors: Balasubramanyam Karanam, Clayton Yates, Ravi Anchoori
Journal: Cancer Research (2022)

Abstract Quadruple negative breast cancer (QNBC), lacking the expression of ER (estrogen receptor), PR (progesterone receptor), HER2 (human epidermal growth factor receptor 2) and AR (androgen receptor), is the breast cancer subtype with the worst prognosis, and QNBC disproportionately afflicts African Americans. It has no standard-of-care treatment targets and thus efficacious and safe treatments are urgently sought for this unmet medical need, and to address the disparity in breast cancer outcomes. The current proposal is motivated by data showing elevated expression of proteasome subunit RPN13 is associated with both African American race and lower survival in QNBC patients, that RPN13 selectively targeted by a small molecule Up284 developed by Up Therapeutics. Both triple negative breast cancer and QNBC cell lines show evidence of greater vulnerability to proteasome inhibitors. However, licensed 20S proteasome inhibitors, e.g. bortezomib, have proven ineffective against solid tumors, with emergence of resistance, and dose limiting toxicities including thrombocytopenia and neutropenia. Up284 has a target and structure designed to overcome the limitations of the licensed drugs with respect to drug resistance. Up284 blocks substrate recognition and deubiquitination rather than just one of the three 20S catalytic activities), poor activity against solid tumors (Up284 has a novel spiro structure with evidence of improved drug access to tumor as compared to peptide-based 20S inhibitors), key toxicities of thrombocytopenia and neutropenia (unlike 20S inhibitors, Up284 does not target the immunoproteasome expressed by hematopoietic cells and does not show these toxicities). Up284 shows broad anticancer activity in vitro, including against QNBC lines with a robust therapeutic index, a promising safety profile and pharmacodynamics, and the ability to control xenograft tumor. By inhibiting proteasome ubiquitin receptor RPN13 function and its associated deubiquitinase activity, Up284 triggers more rapid accumulation and increased molecular weight polyubiquinated protein aggregates than is induced by 20S inhibitors. These toxic misfolded protein aggregates produce an unresolved ER stress, activate the canonical Unfolded Protein Response (UPR) signaling cascade and more rapidly triggers apoptosis than 20S inhibitor. The safety parameters and promising efficacy of Up284 against breast cancer lines encourages us to validate Up284 efficacy in more QNBC lines and animal models. We discuss Up284 efficacy and pharmacological analysis in our presentation. Citation Format: Balasubramanyam Karanam, Clayton Yates, Ravi Anchoori. Up284, a novel inhibitor to treat quadruple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1781.
Abstract 3846: Parkin regulates tumor evasion by controlling antigen processing and presentation through the PTEN/AKT network
Authors: Renzo Perales Linares, Hesham Mohei, Nektaria M. Leli, Silvia Beghi, Nektarios Kostopoulos, Amit Maity, Costantinos Koumenis, Andrea Facciabene
Journal: Cancer Research (2022)

Abstract A growing body of evidence supports the role of Parkin as a tumor suppressor involved in a number of cellular processes, including the downregulation of cell cycle and proliferation, migration, invasion, metastasis, mitophagy, and energy metabolic reprogramming. Indeed, epidemiological, genetic, and bioinformatic studies have shown multiple degrees of defects in the PARK2 gene, localized in human chromosome 6q25-27, a region frequently lost in cancers. In the present study, we show a novel role of Parkin in tumor immune surveillance through dysregulation of the PTEN/PI3k/AKT pathway, involving the modulation of antigen presentation machinery and antitumor-specific CD8+ T cell reactivity. We generated murine and human models that resemble the advanced-stage tumors where Parkin deficiencies are mostly found. In the mouse models, we observed a striking increase of tumor aggressiveness in the absence of Parkin that was associated with loss of antigen presentation and a significant decrease in the infiltration of antitumor CD8+ T cells. Importantly, loss of PARK2 also affected the efficacy of a Tumor-Associated Mitochondria Antigens (TAMAs) based vaccine showing the crucial role of Parkin in tumor development and in the context of antitumor cellular therapeutic strategies. Moreover, we also found that the lack of Parkin in the B16-OVA melanoma model also negatively impacts cytosol-derived antigen presentation and CD8+ T cell immunity. Finally, the analysis of TCGA tumor atlas validates the relevance of PARK2 loss on cancer immunotherapy effectiveness. Thus, during the progression and immunotherapy of cancer, the presence of Parkin mutations that result in loss of its functionality impact antigen presentation and facilitate tumor evasion. Citation Format: Renzo Perales Linares, Hesham Mohei, Nektaria M. Leli, Silvia Beghi, Nektarios Kostopoulos, Amit Maity, Costantinos Koumenis, Andrea Facciabene. Parkin regulates tumor evasion by controlling antigen processing and presentation through the PTEN/AKT network [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3846.
Abstract 3005: Inflammasome-independent pyroptosis mediates DHA-led ovarian cancer cell death
Authors: Ozlem Calbay, Shuang Huang
Journal: Cancer Research (2022)

Abstract Docosahexaenoic acid (DHA) is a natural compound, which exhibits anti-cancer capability in various cancer types in experimental models. Similar to previous reports in other cancer cell types, we demonstrated that DHA inhibited ovarian cancer cell growth by inducing cell death. In our model, distinct from the effect of DHA on other cancer cell types, we revealed that DHA-induced cell death was only slightly blocked by apoptosis inhibitor (caspase 3 inhibitor DEVD). We characterized the mechanism associated with DHA-led cell death and found that DHA-induced cell death was effectively blocked by caspase 1 inhibitor, indicating that DHA kills ovarian cancer cells by inducing pyroptosis. This mechanism was further supported by the observation that Disulfiram, a Gasdermin D inhibitor, prevented DHA-induced cell death and DHA treatment leads to the cleavage of Gasdermin D. Surprisingly, known inflammasome inhibitors did not affect DHA-induced cell death and Gasdermin D cleavage, ruling out the involvement of the inflammasome for caspase 1 activation. Instead, DHA remarkably elevated the amount of both caspase I and cleaved caspase 1 in ovarian cancer cells. This suggests that DHA activates caspase 1 by augmenting the abundance of caspase 1. Furthermore, we showed that DHA increased the level of intracellular reactive oxygen species (ROS). Use of ROS inhibitor (NAC) abrogated DHA-induced pyroptosis. This study uncovers pyroptosis as the mechanism for DHA-induced ovarian cancer cell death and reveals a previously unknown mechanism for caspase 1 activation. Citation Format: Ozlem Calbay, Shuang Huang. Inflammasome-independent pyroptosis mediates DHA-led ovarian cancer cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3005.
Abstract 3228: Body mass index and ovarian cancer: Changes after diagnosis and associations with overall survival
Authors: Alicia Beeghly-Fadiel, Sharon Phillips, George Bukenya, Pranoti Pradhan, Sara Duque, Nneka Anyanwu, Deok-Soo Son, Andrew J. Wilson, Demetra H. Hufnagel, Marta A. Crispens
Journal: Cancer Research (2022)

Abstract Background: While excess adiposity is positively associated with ovarian cancer risk, the relationship with patient prognosis remains to be fully elucidated, especially with regard to changes over time during survivorship. Methods: We assembled a retrospective cohort of tumor registry confirmed ovarian, fallopian tube, and primary peritoneal cancer cases and evaluated peri- and post-diagnosis (±30 days and up to 5 years after, respectively) body mass index (BMI) from electronic medical records (EMR) from the Vanderbilt University Medical Center. Associations with overall survival (OS) were quantified by Hazards Ratios (HRs) and corresponding 95% confidence intervals (CIs) from Cox proportional hazards regression; multivariable adjustment included age, stage, grade, histologic subtype, treatment, race, and year of diagnosis. Results: We evaluated 13,676 peri- and post-diagnosis BMI observations for 616 predominantly Caucasian (87.0%) cases; the majority had serous histology (62.5%), advanced stage (58.1% Stage III or IV), high grade (52.4% poorly or undifferentiated) disease. Compared to peri-diagnosis (median =29.0), BMI was lowest 6 months post-diagnosis (median=27.4) and then gradually increased over time among survivors. In multivariable adjusted models, each 5-unit increase in mean peri-diagnosis BMI corresponded with a nonsignificant increase (HR: 1.07, 95% CI: 0.97-1.18) while higher mean post-diagnosis BMI corresponded to a significantly decreased risk of death (HR: 0.92, 95% CI: 0.84-1.00). Adjusted models that incorporated all peri- and post-diagnosis BMI observations evaluated indicated that each 5-unit increase in BMI was associated with a 15% reduced risk of death (HR: 0.85, 95% CI: 0.77-0.94). Conclusions: Whereas lower adiposity may be beneficial in terms of risk, higher adiposity appears to benefit ovarian cancer survival. Factors including cancer cachexia, weight loss among ill patients, and weight gain among survivors may contribute to this seemingly protective association. Additional research to disentangle the influence of BMI on ovarian cancer outcomes and inform adiposity guidance for ovarian cancer survivors is needed. Citation Format: Alicia Beeghly-Fadiel, Sharon Phillips, George Bukenya, Pranoti Pradhan, Sara Duque, Nneka Anyanwu, Deok-Soo Son, Andrew J. Wilson, Demetra H. Hufnagel, Marta A. Crispens. Body mass index and ovarian cancer: Changes after diagnosis and associations with overall survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3228.
Diffuse “Tree-in-Bud” Pattern on High-Resolution Computed Tomography in Severe Vaping-induced Lung Injury
Authors: Patrick D. Collins, Christopher I. S. Meadows, Boris E. A. Lams, Sangita Agarwal, Duncan L. A. Wyncoll
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Diffuse “Tree-in-Bud” Pattern on High-Resolution Computed Tomography in Severe Vaping-induced Lung Injury." American Journal of Respiratory and Critical Care Medicine, 206(4), pp. 501–502
Abstract 5772: Differences in clinical actionability by comparing mutational landscape of young and old breast cancer patients
Authors: Jiaqi Liu, Ziqi Jia, Gang Liu, Xiang Wang, Qi Meng, Sha Wang, Yang Shao
Journal: Cancer Research (2022)

Abstract Background: Early-onset breast cancer (BC) is associated with poor prognosis, which is also characterized by high recurrence risk, distant metastases and advanced stages at the time of diagnosis. While germline mutations in BRCA1/2 are known to underlie a subset of early-onset BC cases, the clinical and genetic characteristics in other young BC patients remain to be explored. Method: We profiled primary lesions from 440 Chinese female BC patients by using a 425-cancer-gene panel. The population was sub-divided into young (≤40 years old) and old (&amp;gt;40 years old) BC patients according to ages at diagnosis. Young and old BC patients were compared for their associations with genomic aberrations, with focus on existing BC targetable alterations, including those in the ERBB2 gene and PI3K and homologous recombination repair (HRR) pathways. Results: 137 (31.1%) patients presented with BC at a young age (median age=35 [18-40]) and 303 (68.9%) with BC diagnosed at an older age (median age=53 [41-82]) in our study cohort. TP53 (young, 61.3%; old, 67%), PIK3CA (33.6% and 41.3%), and GATA3 (9.5% and 8.3%) were among the top frequently altered genes in both subgroups. A total of 70 patients carried pathogenic germline mutations. Of these, 57.3% were alterations in the HRR pathway genes, including BRCA1/2, WRN, BLM, and PALB2, etc, with comparable frequencies in young and old patients. Germline BRCA1/2 mutations were detected in nine (6.6%) and 23 (7.6%) of the young and old patients, respectively. Somatic BRCA1/2 mutational frequencies were also comparable between young (8.8%) and old (9.9%) patients. Overall, somatic alterations in HRR pathway genes were detected in 32.1% young and 40.6% old BC patients. While similar frequencies of ERBB2 amplification (14.6% vs. 18.2%; P= 0.41) were detected in young and old BC patients, older patients carried more ERBB2 mutations (1.5% vs. 7.3%, P= 0.01). Interestingly, the highest rate of ERBB2 amplification was observed in the 20-30 years age group. Alterations in NF1 (10.6% vs. 3.6%, P=0.02) and PKHD1 (6.9% vs. 2.2%, P=0.04) were more frequent in older patients. Alterations in the PI3K pathway genes were more enriched in the older BC patients with overall mutational frequencies of 55.5% and 68.6% (P=0.01) in young and old subgroups, respectively. Finally, we observed an age-dependent increase in tumor mutational burden. Conclusion: BC in young and old patients exhibited different genomic characteristics that could be taken into consideration for treatment recommendations. Citation Format: Jiaqi Liu, Ziqi Jia, Gang Liu, Xiang Wang, Qi Meng, Sha Wang, Yang Shao. Differences in clinical actionability by comparing mutational landscape of young and old breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5772.
Abstract 4082: Expression of chimeric antigen receptor therapy targets in subpopulations detected by single-cell sequencing of normal cells may contribute to off-tumor toxicity
Authors: Ying Jing, Yuan Liu, Qiang Li, Leng Han
Journal: Cancer Research (2022)

Abstract Chimeric antigen receptor (CAR)-engineered cell therapy, which leverages genetically modified immune cells to generate a tailored immune response, has revolutionized cancer treatment (Dougan et al., 2021; Hong et al., 2020). The number, type and indications of clinical trials for CAR-engineered cell therapies have increased rapidly in recent years (MacKay et al., 2020). However, serious and potentially life-threaten toxicities, such as on-target, off-tumor effects, remain a major limitation of CAR-engineered cell therapies (Dougan et al., 2021; MacKay et al., 2020). To better understand the effects of CAR-directed immunotherapy, a systematic single-cell-level dissection of the expression of divergent CAR targets in various cell types across different normal tissues is urgently required. We analyzed the expression of 591 CAR targets, including 71 that were employed in clinical trials up to January 2021 and 520 that were predicted to have favorable safety profiles (MacKay et al., 2020), in two independent single-cell cohorts, including 342,755 adult cell scRNA-seq data from human cell landscape (HCL) based on Microwell-seq (Han et al., 2020), and 84,363 adult cell scRNA-seq data from adult human cell atlas (AHCA) based on 10× Genomics (He et al., 2020). We used a stringent cutoff by defining a CAR target as a potentially risky gene (PRG) if it was measurable in more than 100 non-immune cells and more than 2% of the total cells in at least three normal tissues. We identified 92 and 88 PRGs from HCL and AHCA by employing this criterion, with 57 PRGs shared in both HCL and AHCA datasets (hypergeometric test p = 7.17×10-29), suggesting the robustness of our analysis. To aid the research community in the design of CAR targets, we developed a user-friendly data portal, CAR target gene toxicity at single-cell level (CARTSC) (https://hanlab.tamhsc.edu/CARTSC/), to allow for browsing and searching the single target and logical ‘and’ design switch expressions at the single-cell level. Citation Format: Ying Jing, Yuan Liu, Qiang Li, Leng Han. Expression of chimeric antigen receptor therapy targets in subpopulations detected by single-cell sequencing of normal cells may contribute to off-tumor toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4082.
Abstract 6297: New biomarker in liquid biopsies from breast and ovarian cancers
Authors: Safaa A. Ibrahim, Valerie Riehl, Kenneth D. Beaman
Journal: Cancer Research (2022)

Abstract Breast and ovarian cancer (BOC) are among the top ten common cancers in females worldwide and remain important causes of death in women. There are shared risk factors between breast and ovarian cancer such as, BRCA1 and BRCA2. Detecting those risk factors are not enough to detect cancer early as approximately half of breast cancers develop in women who have no identifiable breast cancer risk factor other than gender (female) and age (over 40 years). Identification of specific biomarkers in liquid biopsies is required for early detection of BOC. BOC secretes exosomes in large quantities to blood circulation to communicate with different cell types such as immune cells to support cancer growth and metastasis. We detect a significant and readily measurable expression of a specific peptide from the a2 isoform vacuolar ATPase (a2NTD) in the exosomes isolated from the plasma collected from BOC patients. We found that a2NTD is highly expressed in stage III ovarian cancer. In this stage, the tumor spread outside of the abdomen and/or nearby lymph nodes. a2NTD positively correlates with the CA125 levels in plasma. These data show that plasma a2NTD correlates with tumor cell growth and metastasis. In addition, a2NTD associated breast cancer exosome can contribute to the pathophysiology of the disease as it induces PBMCs to secrete cancer promoting factors such as IL-8, CCL-2, and MMP-9. Importantly, those secreted factors promote angiogenesis and tumor cell migration. a2NTD promotes the immunosuppressive properties of neutrophils by stimulating arginase-1 release. Together, this data shows that a2NTD can be a potential diagnostic biomarker and therapeutic target in breast and ovarian cancer. Citation Format: Safaa A. Ibrahim, Valerie Riehl, Kenneth D. Beaman. New biomarker in liquid biopsies from breast and ovarian cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6297.
Abstract SY18-02: Beyond tumor antigen immunogenicity: Determinants of protective immunity induced by therapeutic cancer vaccines
Authors: Lelia Delamarre
Journal: Cancer Research (2022)

Abstract Cancer-specific mutations can generate neoantigens that are recognized as foreign by the immune system and elicit potent T cell responses against cancer. The identification of neoantigens as drivers of effective anti-tumor immunity has promoted the development of neoantigen-based therapeutic strategies, including vaccines and cell-based therapies. One challenge for these approaches is to accurately predict neoantigens. Most mutations are unique to each patient and only a fraction are immunogenic. The generation of large-scale mass spectrometry-based immunopeptidomics training data for the development of deep learning models has resulted in significantly improved computational methods for prediction of neoantigen presentation on HLA. In addition, on-going efforts to characterize antigen determinants involved in TCR recognition may also contribute to further improving immunogenicity prediction. However, induction of neoantigen-specific T cells may not be sufficient for efficacy. We used the MC38 cancer model to characterize the factors associated with effective neoantigen-specific T cell responses after vaccination. We designed two RNA-LPX vaccines (Deca-1 and Deca-2), each encoding 10 MC38 neoantigens. The two vaccines elicited T cell responses with comparable magnitude and functionality. Prophylactic vaccination with either vaccine prevented establishment of MC38 tumors, confirming that vaccine-induced T cells can recognize and kill tumor cells. Surprisingly, while vaccination with Deca-2 was protective in therapeutic settings, vaccination with Deca-1 was unable to reverse growth of established tumors. Neoantigen-specific CD8 T cell migration to the tumor was comparable between the two vaccines, but the phenotypes of the T cells were significantly different. Gene expression analysis revealed specific activation states of T cells that differed according to their antigenic specificity and clonal expansion, suggesting intrinsic differences across different T cell specificities. Remarkably, T cells elicited by Deca-1 exhibited a gene signature of reduced functionality at the tumor site and also in the spleen, the primary site of vaccine activity. Our study has important implications for the development of neoantigen therapies, as it suggests that the properties of the neoantigen/TCR pairs influence the phenotype of vaccine-induced T cells at the tumor site and therapeutic outcome. Furthermore, our results indicate that the tumor may influence the phenotype of vaccine-induced T cells outside the tumor microenvironment. Additional experiments are on-going to further define the exact nature of these determinants. Citation Format: Lelia Delamarre. Beyond tumor antigen immunogenicity: Determinants of protective immunity induced by therapeutic cancer vaccines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY18-02.